Aprepitant (5-([(2R,3S)-2((R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluoro-phenyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one) is an antiemetic compound that belongs to the class of substance P antagonists that mediate their effect by blocking the neurokinin (NK1) receptor. Aprepitant is a selective, high-affinity antagonist at human substance P NK-1 receptors and is manufactured by Merck & Co. (available under the brand name, Emend®). It is available as oral capsules for the prevention and control of acute and delayed chemotherapy induced nausea and vomiting and for prevention of postoperative nausea and vomiting.
Aprepitant is a white to off-white crystalline, solid, with a molecular weight of 534.43 with structure:

Aprepitant is practically insoluble in water, sparingly soluble in ethanol and isopropyl acetate, and slightly soluble in acetonitrile. Typical solubility data of Aprepitant using ethanol as a solvent (with the balance water) arc shown in Table 1 below. As can be seen from the table, pharmaceutically relevant concentrations are typically only achieved at unacceptably high ethanol concentrations.
TABLE 1Ethanol Conc. (v/v)Aprepitant Conc. (mg/mL)100.0001300.0232501.76553.30605.17012.89021.8
To overcome problems associated with poor solubility of aprepitant in pharmaceutical compositions, oral formulations of aprepitant can be prepared and are commercially available as a nanoparticulate composition (EMEND™, Merck) with an average particle size of less than about 1000 nm. However, the bioavailability of the compound when given orally is only about 60-65%.
Several attempts were made to solubility the aprepitant by solid-state manipulation. For example, WO 2007/088483 describes the preparation of amorphous aprepitant, while WO 2007/112457 discloses a mixture of two crystalline forms, namely, Form I and Form II, and pharmaceutical compositions thereof. US 2010/0151035 discloses a pharmaceutical composition of aprepitant containing a polymer and inert, pellets, whereby the dissolution rate of the drug is dependent on particle size of pellets. WO 2007/147160 describes compositions of amorphous aprepitant in the form of a co-precipitate with enhanced solubility of aprepitant, and US 2011/0009362 discloses a solubility enhanced form of aprepitant that involves forming a co-precipitate between the drug and cyclodextrin. However, the stability of such compositions in solution is generally insufficient. These and all other extrinsic materials discussed herein are incorporated herein by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. However, notwithstanding numerous attempts to increase the solubility of aprepitant, aprepitant per se is available only in a formulation for oral administration.
Aprepitant is also available as a water soluble prodrug salt form (e.g., EMEND™ for injection, Merck), fosaprepitant dimeglumine, for intravenous (IV) administration since aprepitant by itself has limited water solubility. Fosaprepitant is a phosphorylated prodrug form of aprepitant and is rapidly converted to aprepitant after IV administration. Prodrug formation of aprepitant molecule involves phosphorylation of the aprepitant molecule followed by salt formation with dimeglumine. Fosaprepitant has been reported to undergo rapid conversion to aprepitant in less than 30 minutes of an IV infusion. Studies have shown the non-inferiority and bioequivalency of fosaprepitant to aprepitant with respect to the prevention and control of acute and delayed chemotherapy induced nausea and vomiting. However, the additional steps required for the synthesis of fosaprepitant add significant complexity and cost to the drug. Furthermore, the commercial formulation of the prodrug of aprepitant, Emend® is reported to be stable only for 24 hours after reconstitution.
In view of the fact that fosaprepitant rapidly converts to the active form in vivo, it would certainly be advantageous from a manufacturing, use, and cost standpoint to formulate aprepitant in a soluble and stable form for parenteral administration. However, and to the best of the inventors' knowledge, no such soluble and stable formulation of aprepitant has been reported. Thus, there is a need for a stable liquid formulation of aprepitant for parenteral delivery.